Study On The Synthesis Of Densely Substituted Pyrimidines From 3,4-dihydropyrimidin-2(1H)-ones

In 1893, Italian chemist Pietro Biginelli reported the synthesis of functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) via three-component condensation reaction of an aromatic aldehyde, urea, and ethyl acetoacetate. In the 1980s, such Biginelli-type dihydropyrimidones have received a considerable amount of attention due to the interesting pharmacological properties associated with this heterocyclic scaffold, and the scope of the original cyclocondensation reaction was gradually extended by variation of all three building blocks, allowing access to a large number of multifunctionalized dihydropyrimidines of this type. In this thesis, the recent developments in the synthesis of DHPMs are reviewed and two new methods for the synthesis of C2-multifunctionalized pyrimidines are described. The research results are summarized below:1. A mild and rapid procedure to the synthesis of C2-substituted pyrimidines was developed by sequential functionalization of easily available Biginelli 3,4-dihydropyrimidine-2(1H)-ones via oxidation, esterification followed by cross-coupling reaction of pyrimidin-2-yl sulfonates with N, S, and O nucleophiles at room temperature. The advantages of this method are mild reaction conditions, fast reaction rate, non-using of metal catalyst. A series of pyrimidin-2-yl sulfonates are excellent precursors for the generation of C2-substituted pyrimidines via displacement of the reactive sulfonate group with different amines, p-thiocresol and alcohols , while phenols provided O-S cleavage products.2. Polyethylene glycol 400 (PEG-400) is found to be an inexpensive, non-toxic, environmentally friendly reaction reaction medium for the esterification reactions and cross-coupling reaction of pyrimidin-2-yl sulfonates with N, S, and O nucleophiles to give C2-substituted pyrimidines.3. The Biginelli 3,4-dihydropyrimidin-2(1H)-one was converted to various C2-multifunctionalized pyrimidines via the dehydrogenation and Mitsunobu reaction using amines, alcohols, phenols and carboxylic acids as nucleophiles. The simplicity (only two-step needed using 3,4-dihydropyrimidinones as starting material) and higher efficiency make this method particularly attractive.